Eunsil Sung KO MIN KYUNG Ju-youngWon JO, YUNJU EunyoungPark HyunjooKim Eunji Choi Ui-jung Jung Jaehyoung Jeon Youngkwang Kim Hyejin Ahn Da-som Choi Choi, Seung hyun Youngeun Hong Hyeyoung Park Hanbyul Lee Yong-Gyu Son Kyeongsu Park Jonghwa Won Soo Jin Oh Seonmin Lee Kyu-pyo Kim Changhoon Yoo Hyun Kyu Song Hyung-seung Jin Jaeho Jung Park, Yoon 2024-01-12T03:00:42Z 2024-01-12T03:00:42Z 2022-08-30 2022-08 1525-0016 https://pubs.kist.re.kr/handle/201004/76637 Several preclinical studies demonstrate that antitumor efficacy of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade can be improved by combination with other checkpoint inhibitors. Lymphocyte-activation gene 3 (LAG-3) is an inhibitory checkpoint receptor involved in T cell exhaustion and tumor immune escape. Here, we describe ABL501, a bispecific antibody targeting LAG-3 and PD-L1 in modulating immune cell responses against tumors. ABL501 that efficiently inhibits both LAG-3 and PD-L1 pathways enhances the activation of effector CD4(+) and CD8(+) T cells with a higher degree than a combination of single anti-LAG-3 and anti-PD-L1. The augmented effector T cell responses by ABL501 resulted in mitigating regulatory-T-cell-mediated immunosuppression. Mechanistically, the simultaneous binding of ABL501 to LAG-3 and PD-L1 promotes dendritic cell (DC) activation and tumor cell conjugation with T cells that subsequently mounts effective CD8(+) T cell responses. ABL501 demonstrates its potent in vivo antitumor efficacy in a humanized xenograft model and with knockin mice expressing human orthologs. The immune profiling analysis of peripheral blood reveals an increased abundance of LAG3(hi)PD-1(hi) memory CD4(+) T cell subset in relapsed cholangiocarcinoma patients after gemcitabine plus cisplatin therapy, which are more responsive to ABL501. This study supports the clinical evaluation of ABL501 as a novel cancer immunotherapeutic, and a first-in-human trial has started (NCT05101109). English Nature Publishing Group LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation Article 10.1016/j.ymthe.2022.05.003 1 Molecular Therapy, v.30, no.8, pp.2800 - 2816 Molecular Therapy 30 8 2800 2816 Y scie scopus 000842995100013 Biotechnology & Applied Microbiology Genetics & Heredity Medicine, Research & Experimental Biotechnology & Applied Microbiology Genetics & Heredity Research & Experimental Medicine Article TARGETING LAG-3 TNF-ALPHA CD8(+) CD4(+) CANCER PD-1 GENE-3 GEMCITABINE EXPRESSION MATURATION